PTKs catalyzes phosphorylation of specific tyrosine residues in various proteins, which residues participate in regulation of cellular growth and differentiation (A. F. Wilks, Progress in Growth Factor Research, 1990, 1, 97-111; S. A. Courtneidge, Dev. Supp. L, 1993, 57-64; J. A. Cooper, Semin. Cell Biol.; 1994, 5(6), 377-387; R. F. Paulson, Semin. Immunol., 1995, 7(4), 267-277; A. C. Chan, Curr, Opin. Immunol., 1996, 8(3), 394-401). Much inappropriate or uncontrolled activation of PTKs i.e., abnormal PTK activity, such as overexpression or mutation, leads to uncontrolled cellular growth and thereby causes many diseases. Known diseases include psoriasis, rheumatoid arthritis, bronchitis, and cancers as well as other diseases such as angiogenesis, atherosclerosis, age-related macular degeneration, diabetic retinopathy and the like. At present, erbB family comprising c-erbB-2, EGFr and erbB-4, is a group of PTKs useful as therapeutic targets, and it shows a potential effect in the treatment of over-proliferative diseases in particular, especially in the treatment of human malignant pathological changes e.g., non-small cell lung cancer, bladder cancer, and head and neck cancer. In addition, enhanced c-erbB-2 activity involves breast cancer, ovarian cancer, gastric cancer and pancreatic cancer. Hence, inhibition of PTKs of erbB family provides a therapy for diseases characterized by abnormal PTKs activity of erbB family. Biological action of PTKs of erbB family as well as relationship thereof with various disorders have been discussed in, e.g., the U.S. Pat. No. 5,773,476, WO 99/35146, M. G. Hung et al., Seminars in Oncology, 26:4, Suppl. 12 (August) 1999, 51-59; Ullrich et al., Cell, 61:203-212, Apr., 20, 1990; Modjitahedi et al., Int. J. of Oncology, 13:335-342, 1998; and J. R. Wooburn, Pharmacol. Ther., 82:2-3, 241-250, 1999.
Some documents record the relevant technology in terms of PTKs inhibitors and/or quinazoline derivatives. For example, WO 9630347 (Chinese patent application CN 96102992.7) concerns some 4-(substituted phenylamino) quinazoline derivatives for treating over-proliferative disorders. WO 9738983 (Chinese patent application CN 97194458.X) provides compounds as irreversible inhibitors of tyrosine kinases. WO 0006555 (Chinese patent application CN 99808949.4) discloses that some substituted quinazoline derivatives have PTKs inhibitory activity. WO 9935146 (Chinese patent application CN 99803887.3) discloses bicyclic heteroaromatic compounds as PTKs inhibitors. WO 2006071017 discloses a series of quinazoline compounds. Chinese patent applications CN 01817895.2, CN 93103566.X, CN 98807303.X, CN 96193526.X, CN 01812051.2, CN 99803887.3, CN 200410089867.5, and CN 03811739.8, and US patents such as U.S. Pat. Nos. 5,521,184, 6,894,051, 6,958,335, 5,457,105, 5,616,582, 5,770,599, 5,747,498, 6,900,221, 6,391,874, 6,713,485, 6,727,256, 6,828,320, and 7,157,466 all mention that a plurality of types of quinazoline compounds have PTKs inhibitory activity. Commercially available drugs include FDA approved Laptinib, Gefitinib, Erlotinib, Imatinib etc. These drugs are directed to different indications and the treatment of only a few particular tumors. With the continuous development of medical diagnosis and therapy levels, the therapy of proliferative diseases, in particular tumors, is more and more specific and targeted, so there is an urgent clinical demand for products which are clearly effective and highly targeted on proliferative diseases and tumors.
Novel compounds having an inhibitory effect on mammalian PTKs, having good biological properties and good formulation adaptability and being useful for the preparation of pharmaceutical compositions that meet requirements during formulation process and have storage stability as well as high bioavailability, will undoubtedly promote therapeutic progress of diseases characterized by abnormal PTKs activity of erbB family and satisfy urgent clinical needs.
In the Chinese patent application CN 200610023526.7, submitted by the applicant on Jan. 20, 2006 and published on Jul. 25, 2007, and in the PCT application WO 2007/082434 submitted on Oct. 20, 2006 and published on Jul. 26, 2007, the applicant presents a series of quinazoline compounds having the formula I:

Intensive studies and explorations of the applicant reveal that the series of compounds have PTKs inhibitory activity. It is particularly stated that N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]quinazolin-6-yl}-acrylamide, as shown in Formula II, has excellent inhibitory activity against erbB-2 kinase. Experiments demonstrate that it has remarkable inhibitory effect on growth of human epidermoid squamous carcinoma cell A431 and human breast cancer cell BT-474 and that it has an obvious anti-tumor effect on human epidermoid squamous carcinoma cell A431 grafted to a nude mouse. These two applications are fully incorporated herein by reference.
After intensive and extensive research and a large amount of tests, the applicant has discovered that salts of N-{-4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]quinazolin-6-yl}-acrylamide have very beneficial properties that solve the solubility problem of the compound in oral administration. In PCT/CN2008/000318 submitted on Feb. 4, 2008, the applicant presents the salt form of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]quinazolin-6-yl}-acrylamide. The application is fully incorporated herein by reference.
By further research, the applicant surprisingly found the stabilizers that have dispersing and/or protective effect on the active ingredient, salts of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]quinazolin-6-yl}-acrylamide. These stabilizers are some high-molecular substances and/or surface active substances that can enhance applicability of the active ingredient to a formulation so that a pharmaceutical composition comprising the active ingredient has good formulation adaptability and improves stability of the formulation. Thus, a pharmaceutical formulation which is stable during storage and has high bioavailability has been prepared, and thereby the present invention is accomplished.